HLA-DR Antibody Design for AML-Selective CAR Immune Cells
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Solution Overview
Problem
Current chimeric antigen receptor T (CAR-T) cells for treating acute myeloid leukemia (AML) are ineffective due to strong blood toxicity from targeting non-specific cell surface antigens, and no AML-specific targets have been identified through transcriptome or proteome analysis.
Innovation Solution
Development of antibodies that recognize HLA-DR, a cancer-specific epitope formed by post-translational changes, and use these antibodies to create CAR-T and CAR-NK cells that specifically target AML cells, avoiding normal hematopoietic stem cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells target common cell surface antigens (CD33, CD123) for AML treatment, then they can recognize and attack leukemia cells, but they cause strong blood toxicity because these antigens are also expressed on normal blood cells
Solution Approach 1:
The patent applies local quality by targeting a specific localized feature (post-translational modification epitope) on the HLA-DR protein that is uniquely present on AML cells. The antibody KG2032 recognizes a conformational epitope formed by abnormal post-translational modifications of HLA-DR on leukemia cells, while normal cells expressing unmodified HLA-DR remain untouched. This localized targeting approach allows selective destruction of cancer cells without affecting normal cells expressing the same base protein.
Solution Approach 2:
The patent utilizes parameter changes by detecting alterations in the biochemical state of the HLA-DR protein through post-translational modifications. The antibody recognizes a conformational change in HLA-DR that occurs specifically in AML cells due to abnormal glycosylation or other post-translational modifications. This parameter-based differentiation (modified vs. unmodified protein state) enables selective targeting of cancer cells while sparing normal cells.
2Adaptability or versatility
If comprehensive transcriptome or proteome analysis is used to search for AML-specific antigens, then a wide range of potential targets can be identified, but no good AML-specific target has been found despite intensive efforts
Solution Approach 1:
The patent replaces the mechanical/biochemical approach of comprehensive proteome analysis with an immunological screening approach. Instead of using mass spectrometry or antibody arrays to identify targets, the patent uses functional antibody screening where hybridoma-derived antibodies are tested for their ability to bind AML cells and mediate cytotoxicity. This substitution of methodology (immunological function-based screening vs. molecular identification) led to the discovery of the HLA-DR target with appropriate specificity.
Solution Approach 2:
The patent uses an intermediary approach by employing hybridoma-derived antibodies as mediators to bridge the gap between antigen identification and therapeutic application. The antibodies serve as intermediaries that naturally select and bind to relevant epitopes on AML cells, and their binding characteristics are then used to identify the underlying target (HLA-DR). This intermediary step simplifies the target identification process compared to direct proteome analysis.
Data Source
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AI summary
An antibody that recognizes HLA-DR or a functional fragment thereof, a chimeric antigen receptor that has the antibody or a functional fragment thereof, an immune cell expressing the chimeric antigen receptor, a multispecific antibody that includes the antibody or a functional fragment thereof and the antigen recognition site for immune cells, or a pharmaceutical composition containing these antibodies and the like.